In this application, we propose to integrate our research in functional genomics and craniofacial morphology/dysmorphology within the FaceBase Consortium. Specifically, we will focus on the development of the mandible and maxilla. Congenital malformations involving these facial bones significantly impact quality of life because our face is our identity. For example, mandibular dysmorphogenesis ranging from agenesis of the jaw to micrognathia is a common malformation and appears in multiple syndromes. Micrognathia not only presents as a facial deformity but can also cause cleft palate and airway obstruction, such as in Pierre-Robin sequence. The maxilla contributes to mid-facial formation. Maxillary hypoplasia is often associated with cleft palate and has been described in more than sixty different syndromes. Despite their importance, the mechanisms that regulate facial bone development are relatively uncharacterized. This is a significant gap in our knowledge and an important opportunity to generate invaluable resources for the research community. The proposed work is a logical progression from our current spoke project within the FaceBase Consortium on palatal development. Over the past five years, we have deposited nearly 200 hard and soft tissue scans and 125 microarray gene expression datasets in the FaceBase hub. These datasets have demonstrated their utility, as shown by other researchers' presentations at major international conferences and publications. Equally importantly, our team has played a significant role in the FaceBase Consortium, the hub website design, data organization and presentation. Building on our experience and in alignment with RFA-DE-14-004, we propose to investigate facial bone development and malformations. In Specific Aim 1, we will perform global and specific gene expression profiling analysis of mandible development, and will integrate these datasets with cell lineage and quantitative 3D dynamic imaging analyses. In collaboration with the ontology group within the FaceBase consortium, we will define anatomical landmarks and morphometric parameters of the developing mandible. In Specific Aim 2, we will expand our gene expression profile analyses in the developing maxilla. We will correlate this information with 3D imaging of the maxilla and define anatomical landmarks and parameters in collaboration with the ontology group within the FaceBase consortium. Our data will facilitate the investigation of the molecular regulatory mechanism of facial bone formation. In Specific Aim 3, using the data generated here, we will investigate the role of the TGF? and Msx1 signaling network in regulating mandible development and test how manipulation of TGF? downstream target genes can prevent and rescue mandible defects in mutant animal models. This study will showcase how our datasets at the hub can facilitate the generation of hypothesis-driven research and collaborations. Because of the prevalence of facial bone defects in orofacial clefting patients and the lack of quantitative studies in this are, our proposed study will fill a void and provide a significant resource for the research community.